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The effects of clonidine, a potent central alpha-adrenergic agonist, and of tolazoline, an alpha-adrenergic antagonist, on the minimal anesthetic concentration (MAC) of halothane were studied in male mongrel dogs. Control halothane MAC was 0.8 +/- 0.04 vol% (determined in each dog by gas chromatography of arterial blood, n = 30). Clonidine, 5 microgram/kg (n = 10) and 20 microgram/kg (n = 10), give slowly intravenously, maximally reduced MAC by 42% (at 2.3 hours after clonidine) and 48% (at 2.6 hours after clonidine) for each dose. In another set of animals (n = 5) an alpha-adrenergic antagonist, tolazoline, 5 mg/kg IV, reversed the clonidine-induced reduction in halothane MAC rapidly and completely. Tolazoline alone, 5 mg/kg, (n = 5) had no significant effect on halothane MAC. Thus, the administration of the central alpha-adrenergic agonist clonidine decreased the required anesthetic concentration of halothane, as defined by MAC, by almost half. This effect, as it is reversed by tolazoline, is likely to be mediated through a central alpha-adrenergic receptor mechanism.

In contrast to reports of the untoward hemodynamic effects of fentanyl and diazepam in intact organisms, we found that neither a bolus of 100 micrograms/kg fentanyl nor the addition of intravenous doses of diazepam, up to and including 1 mg/kg (cumulative dose 2 mg/kg) caused cardiovascular depression in 13 anesthetized dogs after elimination of their sympathetic and parasympathetic tone. There were no significant changes in mean arterial blood pressure, cardiac output, heart rate, peak left ventricular dP/dt, cardiac filling pressures, or systemic vascular resistance. Rapid bolus injection of 3 mg/kg diazepam (cumulative dose 5 mg/kg) caused a significant (P less than 0.05) but transient (time to 50% recovery less than 2 min) decrease in systemic vascular resistance, blood pressure, and dP/dt. When corrected for pressure changed (dP/dt divided by simultaneous left ventricular pressure), the decrease in dP/dt did not attain statistical significance, nor did changes in cardiac output or filling pressures, even after this large dose of diazepam. We conclude that previously reported decreases in hemodynamic function in subjects with intact autonomic function after fentanyl alone, or after the combination of fentanyl and diazepam, are indirect in nature, that is, are caused by a centrally mediated decrease in vasoregulatory (mainly sympathetic) outflow from the central nervous system.

Clinical reports, as well as animal studies, have described cardiovascular and sympathetic stimulation after the administration of naloxone (NX) to reverse opioid-induced respiratory depression. This investigation examines the effect of PaCO2 on hemodynamic and adrenergic responses to NX, by means of 24 experiments carried out in six dogs. Each dog underwent NX reversal of fentanyl (FEN) at three different PaCO2 levels: 20, 35, and 60 mm Hg. In a final series of six experiments, the dogs were exposed to increasing PaCO2 after autonomic block by total spinal anesthesia and vagotomy. During enflurane anesthesia, 50 micrograms/kg FEN decreased mean arterial blood pressure (MAP), heart rate (HR), and plasma concentrations of norepinephrine (NE) and epinephrine (EPI) significantly. NX 0.4 mg promptly returned HR and MAP to baseline or above in all experiments; catecholamine (CA) levels increased only in hypercapnic dogs. Increases in HR were the same in all series. MAP, EPI, and NE levels were significantly greater than pre-FEN baseline values only in hypercapnic dogs 1 minute after NX and were also significantly higher in hypercapnic than in hypocapnic dogs at this time. NE levels were greater in hypercapnic dogs at all time periods after NX. In blocked dogs, neither F nor NX had any effects on hemodynamic functions or plasma CA levels; the institution of hypercapnia caused significant decreases in HR, MAP, and systemic vascular resistance. This direct circulatory depressant action of an elevated PCO2 may have attenuated the indirectly mediated excitatory hemodynamic effects of NX in intact dogs, thus explaining the relatively greater effect of hypercapnia on adrenergic than on hemodynamic responses to reversal.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypotensive effects of the intravenous injection of adenine compounds [adenosine triphosphate (ATP), adenosine] were compared with those of sodium nitroprusside (SNP) in rabbits during light, stable halothane anesthesia. ATP and adenosine were almost equipotent in their effects on blood pressure and heart rate. The hypotensive potencies of ATP and adenosine were approximately 1/6 (bolus injection) and 1/40 (continuous infusion) that of SNP, but the adenine compounds had a more rapid onset of action and shorter recovery times than SNP. With bolus injection, SNP invariably caused a baroreceptor-mediated reflex increase in heart rate. In contrast, ATP and adenosine caused a dose-related decrease in heart rate and hypotension. With continuous infusion, ATP and adenosine produced immediate onset of hypotension without tachycardia. Blood pressure remained remarkably stable throughout the infusion; neither tachyphylaxis nor rebound hypertension were observed. Thus, the adenine compounds offer possible advantages over SNP as they are physiologic agents with little or no acute toxicity and may be devoid of tachycardia, tachyphylaxis, and rebound hypertension.

A double-blind study comparing four narcotic analgesics of different potencies, meperidine, morphine, fentanyl, and sufentanil, was performed on consenting patients undergoing general or orthopedic surgery under balanced anesthesia. Blood pressure, measured through an indwelling arterial catheter, was recorded continuously, as were ECG and heart rates. The narcotics, made up in equipotent concentrations, were given as indicated by hemodynamic and clinical signs. Arterial blood samples were taken before and after induction, after intubation, before and after incision, at intervals during the operation, and postoperatively. Hemodynamic values and plasma levels of catecholamines during and after induction, intubation, incision, and throughout the operation were least in patients given sufentanil and greatest in those who received morphine or meperidine. Heart rates increased significantly after induction with meperidine and were significantly higher after intubation in morphine-treated and meperidine-treated patients than they were in patients receiving sufentanil. Intraoperatively, mean arterial blood pressure, rate-pressure product, and plasma norepinephrine levels were lowest in patients receiving sufentanil. Intraoperative plasma epinephrine levels were lowest in patients receiving sufentanil and meperidine. Because of increases in blood pressure, heart rate, or both to greater than 15% above control values, supplementation with a potent inhalational agent was necessary in 38%, 30%, and 29% of the patients given meperidine, morphine, and fentanyl, respectively. No sufentanil patient required supplementation. Side effects, including histamine release accompanied by tachycardia and hypotension, were most frequent and most severe in patients who received meperidine. After extubation, marked increases in heart rate, blood pressure, and plasma norepinephrine and epinephrine occurred in some patients in each group. The incidence of postoperative respiratory depression was greatest in patients given morphine (mean dose of naloxone 8.6 micrograms/kg) and least with sufentanil (mean dose of naloxone 1.8 micrograms/kg) and fentanyl (3.2 micrograms/kg naloxone).

A 50-micrograms/kg dose of fentanyl, given intravenously in divided doses to dogs under enflurane-nitrous oxide anesthesia caused sharp decreases in heart rate (HR), arterial blood pressure (AP), left ventricular dP/dt, and plasma levels of catecholamines. Naloxone, 20 micrograms/kg given 65-70 min later, completely and rapidly reversed these changes. Because the cardiovascular effects of fentanyl and naloxone occurred in unparalyzed animals under surgical anesthesia without eliciting any motor responses, it seems unlikely that they can be ascribed to changes in awareness and surgical stimulation, especially pain. The brief duration of exposure to the narcotic makes it improbable that the naloxone response is due to acute dependence and precipitated withdrawal. Pretreatment with 20 micrograms/kg of atropine only attenuated the decrease in HR, indicating a minor role of vagal mechanisms under these conditions. Administration of 20 micrograms/kg of clonidine by slow infusion after fentanyl further reduced sympathetic activity and greatly attenuated the naloxone response. Injection of 5 mg/kg of tolazoline after administration of clonidine produced massive cardiovascular stimulation by antagonizing clonidine and unmasking the naloxone reversal of fentanyl. Thus, in fully anesthetized dogs, fentanyl decreased the level of cardiovascular function mainly by reducing sympathetic activity. This effect does not seem to be secondary to analgesia or other sensory depressant effects of the narcotic, but rather to an action on central opioid-sensitive mechanisms regulating cardiovascular function.

In chloralose-anesthetized dogs the hypotensive and reflex cardiovascular responses to infusions of sodium nitroprusside were studied before and during halothane and enflurane, and before after divided doses of cryptenamine. The latter drug, a mixture of hypotensive veratrum alkaloids, lowers blood pressure reflexly by acting on afferent receptors (baroreceptors). Control infusions of nitroprusside, which caused 10% to 15% decreases im mean arterial blood pressure, markedly increased heart rate, myocardial contractility, cardiac output, rate-pressure product, and left ventricular minute work in spite of decreases in peripheral vascular resistance. Except for increases in contractility, these reflexly mediated effects were not blocked by the addition of 1% halothane or 2% enflurane. Cryptenamine, on the other hand, potentiated nitroprusside-induced hypotension, markedly diminished increases in heart rate, and eliminated increases in myocardial contractility, rate-pressure product, and left ventricular work. Measurements of cardiovascular function returned promptly to preinfusion values when the nitroprusside was stopped. We conclude that under conditions when a high degree of central vasomotor tone is present, homeostatic reflexes may counteract the direct vasodilator effect of nitroprusside, resulting in the need for a greater dose of nitroprusside and obviating the expected beneficial effects on myocardial oxygen supply/demand ratio. Combining cryptenamine with nitroprusside eliminates these problems and at the same time allows retention of the evanescent action of nitroprusside.

Histamine release and hemodynamic changes associated with four narcotics were studied in 60 adults (28 men, 32 women) scheduled for general surgery under balanced anesthesia. Under double-blind conditions, incremental equipotent doses of meperidine, morphine, fentanyl, or sufentanil were administered IV for induction of anesthesia, prior to thiopental, succinylcholine, and intubation. Arterial blood samples were drawn before and 1, 6, and 20 min after narcotic administration. Of the 16 patients given meperidine (mean dose 4.3 +/- 0.2 (SEM) mg/kg), five (31%) had clinical signs (hypotension, tachycardia, erythema) and elevations in plasma histamine levels ranging from 3.2 to 49.7 ng/ml 1 min after narcotic administration. Plasma epinephrine levels at this time were also elevated in these five patients. One of the ten patients given morphine (0.6 +/- 0.02 mg/kg) developed hypotension, tachycardia, and an increase in plasma histamine level to 12.4 ng/ml. None of 34 patients given either fentanyl (7 +/- 0.4 micrograms/kg) or sufentanil (1.3 +/- 0.1 microgram/kg) had clinical signs of histamine release or elevations of plasma histamine levels. In the six patients in whom histamine release occurred, there was a significant correlation between the histamine levels at 1 min and the magnitude of change in heart rate, blood pressure, and plasma epinephrine level. All six histamine releasers were young women, ranging in age from 18 to 35 yr. Histamine release occurred more frequently after meperidine than after the other narcotics, including morphine, and the degree of hemodynamic compromise was related to the increase in plasma histamine concentration.

Supplementation of the antihypertensive action of the peripheral vasodilator sodium nitroprusside (SNP) with clonidine, a centrally-acting agent, was studied in ten dogs anesthetized with isoflurane to evaluate the efficacy of clonidine for reducing the amount of SNP required during induced hypotension. The dose of SNP required to lower mean arterial blood pressure (MAP) by 40% was determined prior to the administration of intravenous clonidine (control), and after incremental doses of 1, 4, and 15 micrograms/kg. After each dose of clonidine, hypotension was induced with SNP and maintained for 30 min, followed by a 30-min recovery period. Plasma levels of norepinephrine (NE) and epinephrine (EPI) were determined before hypotension, at 5 min and 30 min during hypotension, and at 5 min and 30 min during recovery. During the control period (no clonidine), SNP-induced hypotension resulted in increases in plasma catecholamine levels, with larger increases in EPI (from 70 +/- 26 to 851 +/- 140 pg/ml, at 30 min) than NE (from 171 +/- 26 to 334 +/- 58 pg/ml, at 30 min). There was no significant difference between the control MAP and the MAP after each incremental dose of clonidine. In these anesthetized dogs with low sympathetic tone there was no significant decrease in EPI levels after administration of up to 20 micrograms/kg of clonidine. Increasing doses of clonidine correlated inversely with depression in catecholamine output during induced hypotension and the dose of SNP required to produce this hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)